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Journal Club of Scientist-Recommended Papers: May 1, 2005

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RNA Polymerase IV Directs Silencing of Endogenous DNA
Herr AJ, Jensen MB, Dalmay T, Baulcombe DC. Science. 2005 Feb 24.

Plant Nuclear RNA Polymerase IV Mediates siRNA and DNA Methylation-Dependent Heterochromatin Formation
Onodera Y, Haag J, Ream T, Costa Nunes P, Pontes O, Pikaard C. Cell. 2005 March 11; 120, 613-622.

These two papers address a plant-specific RNA polymerase known as Pol IV (all eukaryotes have three nuclear DNA-dependent RNA polymerases, namely, Pol I, II, and III). In the Science paper, researchers at the Sainsbury Laboratory of the John Innes Centre in Norwich, UK, show how Pol IV silences certain transposons and repetitive DNA in a short interfering RNA pathway involving RNA-dependent RNA polymerase 2 and Dicer-Like 3. The authors conclude that the existence of this distinct silencing polymerase may explain the involvement of an RNA silencing pathway in the maintenance of transcriptional silencing.

In the Cell paper, corresponding author Craig Pikaard, a biologist at Washington University in St. Louis, writes that the data in the paper suggest that Pol IV helps produce siRNAs that target de novo cytosine methylation events required for facultative heterochromatin formation and higher-order heterochromatin associations. Shiv Grewal at NCI adds that the results presented in these papers are important for RNAi researchers because they suggest that low-level transcription of transposable elements by RNA polymerase might be essential for generating small interfering RNAs, which then help target heterochromatin complexes.

Shiv Grewal
Senior Investigator
Center for Cancer Research
National Cancer Institute

 

Signal in noise: evaluating reported reproducibility of serum proteomic tests for ovarian cancer. Baggerly KA, Morris JS, Edmonson SR, Coombes KR, J Natl Cancer Inst. 2005 Feb 16;97(4):307-9.

 

In this report, the authors, at MD Anderson Cancer Center in Houston, write critically of the 2002 Liotta/Petricoin paper in The Lancet that presented data on a proteomic profiling approach to diagnosing early-stage ovarian cancer in serum. That publication reported good classification in one dataset using results from training on a much earlier dataset, but its authors have since reported that they did not perform the analysis as described, say Keith Baggerly and his colleagues at MD Anderson. Baggerly says his group’s analysis revealed that the pattern that enabled successful classification is biologically implausible and that the method, properly applied, does not classify the data accurately. The method used in previously published studies does not establish reproducibility and performs no better than chance for classifying the second dataset, in part because the second dataset is easy to classify correctly, the authors add. In conclusion, Baggerly says that the reproducibility of the proteomic profiling approach has yet to be established.

Michael A. Tainsky
Director, Program in Molecular Biology and Human Genetics
Karmanos Cancer Institute
Wayne State University

 

 

Silencing mutant SOD1 using RNAi protects against neurodegeneration and extends survival in an ALS model. Ralph GS, Radcliffe P, Day DM, Carthy JM, Leroux MA, Lee DCP, Wong LF, Bilsland LG, Greensmith L, Kingsman SM, Mitrophanous KA, Mazarakis ND, and Azzouz M, Nature Medicine 11, 429 - 433 (2005).

 

The paper by Ralph et al. describes the use of an EIAV based lentiviral vector to direct the expression of a shRNA targeting the mutant form of human SOD1 (SOD1G93A). Upon intramuscular injection and retrograde transport the authors show decreased expression levels of SOD1 in the ventral horn of the lumbar spinal cord and, as a consequence, a delayed onset of motor symptoms from less than a 100 to over 200 days. As striking is the increased survival of these animals from around 130 days to more than 220 days.

This study elegantly describes the use of a vector-based RNAi in a clinical setting, and it shows that directly using the shRNA vector to target the specific factor underlying the disease can have great therapeutic benefits, says Roderick Beijersbergen at the Netherlands Cancer Institute. Newly identified gene targets for a specific disease can potentially be targeted by the very identical shRNA used to find the particular gene, and more importantly, previously identified genes in disease can be used in the same manner, he adds. One concern is the method of delivery, but the use of a non-invasive method used in this study boosts the expectations for the use of vector based RNAi in the clinic, he says.

Roderick L. Beijersbergen
Division of Molecular Carcinogenesis
The Netherlands Cancer Institute

 

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